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1.
Zhonghua Yan Ke Za Zhi ; 60(6): 547-558, 2024 Jun 11.
Article in Chinese | MEDLINE | ID: mdl-38825955

ABSTRACT

With the increasing prevalence of myopia among adolescents, the pathogenesis of this condition has garnered significant attention. Studies have discovered the expression of various hormone receptors in ocular tissues of both animals and humans. Additionally, changes in hormone levels accompany the development of myopia, although the exact relationships remain inconclusive. This article reviews the potential influences and mechanisms of action of endogenous hormones such as melatonin, serotonin, insulin, glucagon, sex hormones, vitamin D, and prostaglandins in ocular tissues including the retina, choroid, and sclera. It elaborates on the relationship between fluctuations in these hormone levels and the progression of myopia, aiming to provide guidance for exploring targets for myopia prevention and control.


Subject(s)
Melatonin , Myopia , Humans , Myopia/metabolism , Melatonin/metabolism , Vitamin D/metabolism , Serotonin/metabolism , Insulin/metabolism , Glucagon/metabolism , Animals , Gonadal Steroid Hormones/metabolism , Prostaglandins/metabolism , Hormones/metabolism , Retina/metabolism
2.
Elife ; 122024 May 03.
Article in English | MEDLINE | ID: mdl-38700926

ABSTRACT

The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of ß-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and ß-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell ß-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.


Subject(s)
Diabetes Mellitus, Type 2 , Glucagon , Glucose , Insulin Secretion , Mice, Inbred C57BL , Animals , Male , Mice , Animals, Newborn , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Glucagon/metabolism , Glucose/metabolism , Homeostasis , Insulin/metabolism , Insulin Secretion/drug effects , Insulin Secretion/genetics , Islets of Langerhans/metabolism , Mutation , Potassium Channels/metabolism , Potassium Channels/genetics
3.
PLoS One ; 19(5): e0298239, 2024.
Article in English | MEDLINE | ID: mdl-38691547

ABSTRACT

The sweet taste receptor, TAS1R2-TAS1R3, is expressed in taste bud cells, where it conveys sweetness, and also in intestinal enteroendocrine cells, where it may facilitate glucose absorption and assimilation. In the present study, our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism bidirectionally via hyperactivation with 5 mM sucralose (n = 12) and inhibition with 2 mM sodium lactisole (n = 10) in mixture with 75 g glucose loads during oral glucose tolerance tests (OGTTs) in healthy humans. Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants' sweet taste responses to sucralose and their sensitivities to lactisole sweetness inhibition. The addition of sucralose to glucose elevated plasma insulin responses to the OGTT (F(1, 11) = 4.55, p = 0.056). Sucralose sweetness ratings were correlated with early increases in plasma glucose (R2 = 0.41, p<0.05), as well as increases in plasma insulin (R2 = 0.38, p<0.05) when sucralose was added to the OGTT (15 minute AUC). Sensitivity to lactisole sweetness inhibition was correlated with decreased plasma glucose (R2 = 0.84, p<0.01) when lactisole was added to the OGTT over the whole test (120 minute AUC). In summary, stimulation and inhibition of the TAS1R2-TAS1R3 receptor demonstrates that TAS1R2-TAS1R3 helps regulate glucose metabolism in humans and may have translational implications for metabolic disease risk.


Subject(s)
Benzene Derivatives , Blood Glucose , Glucose Tolerance Test , Insulin , Receptors, G-Protein-Coupled , Sucrose , Sucrose/analogs & derivatives , Humans , Receptors, G-Protein-Coupled/metabolism , Male , Adult , Female , Sucrose/metabolism , Blood Glucose/metabolism , Insulin/metabolism , Insulin/blood , Taste/physiology , Young Adult , Thiazoles/pharmacology , Glucose/metabolism , Glucagon/metabolism , Glucagon/blood , Sweetening Agents/pharmacology
4.
PLoS One ; 19(5): e0304086, 2024.
Article in English | MEDLINE | ID: mdl-38771849

ABSTRACT

Recently, the first generic glucagon for injection was approved for the treatment of severe hypoglycemia. Unlike its brand name recombinant glucagon, the generic glucagon is synthetic. Since glucagon has a high propensity to form aggregates in solution, it is essential to assess the aggregation profile of the synthetic glucagon compared to the recombinant glucagon. In this study, two robust separation methods, size-exclusion chromatography (SEC-HPLC) and field-flow fractionation coupled with a multi-angle light scattering detector (FFF-MALS), were employed to characterize generic and brand glucagon aggregation in six lots (three newly released, three expired). The presence of aggregation in samples was determined from the generated chromatograms and analyzed. The study showed that both products have comparable aggregation profiles. The SEC-HPLC demonstrated that in both glucagon versions, the expired lots had a higher percentage of dimers than the newly released lots, but even at expiration, the amount was negligible (∼0.1%). The FFF-MALS method did not detect any dimers or higher molecular weight aggregates. Further evaluation of the detection limit found that FFF-MALS was unable to detect aggregates at amounts lower than 0.5% of total glucagon. The negligible amounts of dimer detected in the generic and brand glucagon indicate that both versions are physically stable and are not prone to aggregation under clinically relevant conditions.


Subject(s)
Chromatography, Gel , Glucagon , Protein Aggregates , Glucagon/chemistry , Glucagon/analysis , Chromatography, High Pressure Liquid/methods , Chromatography, Gel/methods , Scattering, Radiation , Humans , Light
5.
Int J Mol Sci ; 25(10)2024 May 07.
Article in English | MEDLINE | ID: mdl-38791099

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.


Subject(s)
Amyotrophic Lateral Sclerosis , Biomarkers , Insulin , Islet Amyloid Polypeptide , Humans , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/blood , Male , Female , Middle Aged , Aged , Islet Amyloid Polypeptide/metabolism , Islet Amyloid Polypeptide/blood , Cross-Sectional Studies , Biomarkers/blood , Insulin/metabolism , Insulin/blood , Disease Progression , Leptin/blood , Leptin/metabolism , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide 1/blood , C-Peptide/blood , C-Peptide/metabolism , Ghrelin/metabolism , Ghrelin/blood , Glucagon/blood , Glucagon/metabolism , Adult , Hormones/metabolism , Hormones/blood
6.
Eur J Endocrinol ; 190(6): 446-457, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38781444

ABSTRACT

OBJECTIVE: The metabolic phenotype of totally pancreatectomised patients includes hyperaminoacidaemia and predisposition to hypoglycaemia and hepatic lipid accumulation. We aimed to investigate whether the loss of pancreatic glucagon may be responsible for these changes. METHODS: Nine middle-aged, normal-weight totally pancreatectomised patients, nine patients with type 1 diabetes (C-peptide negative), and nine matched controls underwent two separate experimental days, each involving a 150-min intravenous infusion of glucagon (4 ng/kg/min) or placebo (saline) under fasting conditions while any basal insulin treatment was continued. RESULTS: Glucagon infusion increased plasma glucagon to similar high physiological levels in all groups. The infusion increased hepatic glucose production and decreased plasma concentration of most amino acids in all groups, with more pronounced effects in the totally pancreatectomised patients compared with the other groups. Glucagon infusion diminished fatty acid re-esterification and tended to decrease plasma concentrations of fatty acids in the totally pancreatectomised patients but not in the type 1 diabetes patients. CONCLUSION: Totally pancreatectomised patients were characterised by increased sensitivity to exogenous glucagon at the level of hepatic glucose, amino acid, and lipid metabolism, suggesting that the metabolic disturbances characterising these patients may be rooted in perturbed hepatic processes normally controlled by pancreatic glucagon.


Subject(s)
Diabetes Mellitus, Type 1 , Glucagon , Liver , Pancreatectomy , Humans , Glucagon/blood , Glucagon/metabolism , Male , Middle Aged , Female , Liver/metabolism , Liver/drug effects , Adult , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/blood , Lipid Metabolism/drug effects , Blood Glucose/metabolism , Blood Glucose/drug effects , Amino Acids/metabolism , Amino Acids/administration & dosage , Amino Acids/blood , Glucose/metabolism
7.
Sci Rep ; 14(1): 12430, 2024 05 30.
Article in English | MEDLINE | ID: mdl-38816541

ABSTRACT

Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.


Subject(s)
Corticosterone , Dinoprostone , Epinephrine , Fibroblast Growth Factors , Glucagon , Linoleic Acids, Conjugated , Mice, Transgenic , Animals , Female , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , Mice , Linoleic Acids, Conjugated/pharmacology , Linoleic Acids, Conjugated/metabolism , Corticosterone/metabolism , Dinoprostone/metabolism , Glucagon/metabolism , Epinephrine/metabolism , Thermogenesis/drug effects , Thermogenesis/genetics , Male , Lipid Metabolism/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/drug effects , Fatty Liver/metabolism , Fatty Liver/genetics , Lipolysis/drug effects , Hypertriglyceridemia/metabolism , Hypertriglyceridemia/genetics , Adiposity/drug effects
8.
Sci Rep ; 14(1): 8058, 2024 04 05.
Article in English | MEDLINE | ID: mdl-38580678

ABSTRACT

In this paper, we propose a fractional-order mathematical model to explain the role of glucagon in maintaining the glucose level in the human body by using a generalised form of a fractal fractional operator. The existence, boundedness, and positivity of the results are constructed by fixed point theory and the Lipschitz condition for the biological feasibility of the system. Also, global stability analysis with Lyapunov's first derivative functions is treated. Numerical simulations for fractional-order systems are derived with the help of Lagrange interpolation under the Mittage-Leffler kernel. Results are derived for normal and type 1 diabetes at different initial conditions, which support the theoretical observations. These results play an important role in the glucose-insulin-glucagon system in the sense of a closed-loop design, which is helpful for the development of artificial pancreas to control diabetes in society.


Subject(s)
Diabetes Mellitus, Type 1 , Insulins , Humans , Glucagon , Diabetes Mellitus, Type 1/drug therapy , Models, Theoretical , Glucose
9.
Front Endocrinol (Lausanne) ; 15: 1295677, 2024.
Article in English | MEDLINE | ID: mdl-38572473

ABSTRACT

The liver plays pivotal roles in nutrient metabolism, and correct hepatic adaptations are required in maternal nutrient metabolism during pregnancy. In this review, hepatic nutrient metabolism, including glucose metabolism, lipid and cholesterol metabolism, and protein and amino acid metabolism, is first addressed. In addition, recent progress on maternal hepatic adaptations in nutrient metabolism during pregnancy is discussed. Finally, the factors that regulate hepatic nutrient metabolism during pregnancy are highlighted, and the factors include follicle-stimulating hormone, estrogen, progesterone, insulin-like growth factor 1, prostaglandins fibroblast growth factor 21, serotonin, growth hormone, adrenocorticotropic hormone, prolactin, thyroid stimulating hormone, melatonin, adrenal hormone, leptin, glucagon-like peptide-1, insulin glucagon and thyroid hormone. Our vision is that more attention should be paid to liver nutrient metabolism during pregnancy, which will be helpful for utilizing nutrient appropriately and efficiently, and avoiding liver diseases during pregnancy.


Subject(s)
Insulin , Liver , Pregnancy , Female , Humans , Liver/metabolism , Insulin/metabolism , Growth Hormone/metabolism , Glucagon/metabolism , Nutrients
10.
Endocr Relat Cancer ; 31(5)2024 May 01.
Article in English | MEDLINE | ID: mdl-38631379
11.
J Endocrinol ; 261(3)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38579751

ABSTRACT

Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon is a key metabolic regulator, and its actions include the reduction of liver fat through direct and indirect means. Chronic glucagon signalling deficiency is associated with hyperaminoacidaemia, hyperglucagonaemia and increased circulating levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF-21). Reduction in glucagon activity decreases hepatic amino acid and triglyceride catabolism; metabolic effects include improved glucose tolerance, increased plasma cholesterol and increased liver fat. Conversely, glucagon infusion in healthy volunteers leads to increased hepatic glucose output, decreased levels of plasma amino acids and increased urea production, decreased plasma cholesterol and increased energy expenditure. Patients with MASLD share many hormonal and metabolic characteristics with models of glucagon signalling deficiency, suggesting that they could be resistant to glucagon. Although there are few studies of the effects of glucagon infusion in patients with obesity and/or MASLD, there is some evidence that the expected effect of glucagon on amino acid catabolism may be attenuated. Taken together, this evidence supports the notion that glucagon resistance exists in patients with MASLD and may contribute to the pathogenesis of MASLD. Further studies are warranted to investigate the direct effects of glucagon on metabolism in patients with MASLD.


Subject(s)
Fatty Liver , Glucagon , Humans , Glucagon/metabolism , Glucagon/blood , Fatty Liver/metabolism , Obesity/metabolism , Fibroblast Growth Factors/metabolism , Liver/metabolism , Glucagon-Like Peptide 1/metabolism , Animals
12.
Am J Physiol Gastrointest Liver Physiol ; 326(6): G676-G686, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38591131

ABSTRACT

The motility of the gastrointestinal tract is coordinated in part by rhythmic slow waves, and disrupted slow-wave patterns are linked to functional motility disorders. At present, there are no treatment strategies that primarily target slow-wave activity. This study assessed the use of pacing to suppress glucagon-induced slow-wave dysrhythmias in the small intestine. Slow waves in the jejunum were mapped in vivo using a high-resolution surface-contact electrode array in pigs (n = 7). Glucagon was intravenously administered to induce hyperglycemia. Slow-wave propagation patterns were categorized into antegrade, retrograde, collision, pacemaker, and uncoupled activity. Slow-wave characteristics such as period, amplitude, and speed were also quantified. Postglucagon infusion, pacing was applied at 4 mA and 8 mA and the resulting slow waves were quantified spatiotemporally. Antegrade propagation was dominant throughout all stages with a prevalence of 55 ± 38% at baseline. However, glucagon infusion resulted in a substantial and significant increase in uncoupled slow waves from 10 ± 8% to 30 ± 12% (P = 0.004) without significantly altering the prevalence of other slow-wave patterns. Slow-wave frequency, amplitude, and speed remained unchanged. Pacing, particularly at 8 mA, significantly suppressed dysrhythmic slow-wave patterns and achieved more effective spatial entrainment (85%) compared with 4 mA (46%, P = 0.039). This study defined the effect of glucagon on jejunal slow waves and identified uncoupling as a key dysrhythmia signature. Pacing effectively entrained rhythmic activity and suppressed dysrhythmias, highlighting the potential of pacing for gastrointestinal disorders associated with slow-wave abnormalities.NEW & NOTEWORTHY Glucagon was infused in pigs to induce hyperglycemia and the resulting slow-wave response in the intact jejunum was defined in high resolution for the first time. Subsequently, with pacing, the glucagon-induced dysrhythmias were suppressed and spatially entrained for the first time with a success rate of 85%. The ability to suppress slow-wave dysrhythmias through pacing is promising in treating motility disorders that are associated with intestinal dysrhythmias.


Subject(s)
Gastrointestinal Motility , Glucagon , Jejunum , Animals , Swine , Gastrointestinal Motility/physiology , Jejunum/physiopathology , Intestine, Small/physiopathology , Female , Hyperglycemia/therapy , Male
13.
J Endocrinol ; 261(3)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38593829

ABSTRACT

Pancreatic alpha cell activity and glucagon secretion lower as glucose levels increase. While part of the decrease is regulated by glucose itself, paracrine signaling by their neighboring beta and delta cells also plays an important role. Somatostatin from delta cells is an important local inhibitor of alpha cells at high glucose. Additionally, urocortin 3 (UCN3) is a hormone that is co-released from beta cells with insulin and acts locally to potentiate somatostatin secretion from delta cells. UCN3 thus inhibits insulin secretion via a negative feedback loop with delta cells, but its role with respect to alpha cells and glucagon secretion is not understood. We hypothesize that the somatostatin-driven glucagon inhibition at high glucose is regulated in part by UCN3 from beta cells. Here, we use a combination of live functional Ca2+ and cAMP imaging as well as direct glucagon secretion measurement, all from alpha cells in intact mouse islets, to determine the contributions of UCN3 to alpha cell behavior. Exogenous UCN3 treatment decreased alpha cell Ca2+ and cAMP levels and inhibited glucagon release. Blocking endogenous UCN3 signaling increased alpha cell Ca2+ by 26.8 ± 7.6%, but this did not result in increased glucagon release at high glucose. Furthermore, constitutive deletion of Ucn3 did not increase Ca2+ activity or glucagon secretion relative to controls. UCN3 is thus capable of inhibiting mouse alpha cells, but, given the subtle effects of endogenous UCN3 signaling on alpha cells, we propose that UCN3-driven somatostatin may serve to regulate local paracrine glucagon levels in the islet instead of inhibiting gross systemic glucagon release.


Subject(s)
Glucagon-Secreting Cells , Glucagon , Paracrine Communication , Urocortins , Animals , Urocortins/metabolism , Urocortins/genetics , Glucagon-Secreting Cells/metabolism , Glucagon-Secreting Cells/drug effects , Mice , Glucagon/metabolism , Glucose/metabolism , Calcium/metabolism , Male , Mice, Inbred C57BL , Cyclic AMP/metabolism , Somatostatin/pharmacology , Somatostatin/metabolism
14.
ACS Biomater Sci Eng ; 10(5): 3086-3096, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38588325

ABSTRACT

The timely administration of glucagon is a standard clinical practice for the treatment of severe hypoglycemia. However, the process involves cumbersome steps, including the reconstitution of labile glucagon and filling of the syringe, which cause considerable delays in emergency situations. Moreover, multiple dosages are often required to prevent the recurrence of the hypoglycemic episode because of the short half-life of glucagon in plasma. Herein, we develop a glucagon-loaded long-dissolving microneedle (GLMN) patch that exhibits the properties of fast onset and sustained activity for the effective treatment of severe hypoglycemia. Three types of MN patches were fabricated with different dimensions (long, medium, and short). The longer MN patch packaged a higher dosage of glucagon and exhibited supreme mechanical strength compared to the shorter one. Additionally, the longer MN patch could insert more deeply into the skin, resulting in higher permeability of glucagon across the skin tissue and more rapid systemic absorption as compared with the shorter MN patch. The GLMN patch was observed to reverse the effects of hypoglycemia within 15 min of application in animal models (specifically, rat and rhesus monkey models) and maintained long-term glycemic control, owing to highly efficient drug permeation and the drug reservoir effect of the MN base. The current study presents a promising strategy for the rapid reversal of severe hypoglycemia that exhibits the desirable properties of easy use, high efficiency, and sustained action.


Subject(s)
Glucagon , Hypoglycemia , Macaca mulatta , Needles , Animals , Glucagon/administration & dosage , Glucagon/pharmacokinetics , Hypoglycemia/drug therapy , Hypoglycemia/blood , Rats , Male , Rats, Sprague-Dawley , Transdermal Patch , Administration, Cutaneous , Drug Delivery Systems/instrumentation , Blood Glucose/analysis , Blood Glucose/drug effects
15.
Peptides ; 176: 171213, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38604379

ABSTRACT

Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2 mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.


Subject(s)
Adrenocorticotropic Hormone , Glucagon , Glycopeptides , Humans , Glycopeptides/metabolism , Glucagon/metabolism , Glucagon/blood , Adrenocorticotropic Hormone/blood , Adrenocorticotropic Hormone/metabolism , Male , Adult , Female , Pituitary Gland/metabolism , Pituitary Gland/drug effects , Hydrocortisone/blood , Receptors, Glucagon/metabolism , Human Growth Hormone/metabolism , Growth Hormone/metabolism , Growth Hormone/blood , Middle Aged
16.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167185, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38653360

ABSTRACT

OBJECTIVE: Glucagon is a critical hormone regulating glucose metabolism. It stimulates the liver to release glucose under low blood sugar conditions, thereby maintaining blood glucose stability. Excessive glucagon secretion and hyperglycemia is observed in individuals with diabetes. Precise modulation of glucagon is significant to maintain glucose homeostasis. Piezo1 is a mechanosensitive ion channel capable of converting extracellular mechanical forces into intracellular signals, thus regulating hormonal synthesis and secretion. This study aims to investigate the role of Piezo1 in regulating glucagon production in α cells. METHODS: The effects of Piezo1 on glucagon production were examined in normal- or high-fat diet fed α cell-specific Piezo1 knockout mice (Gcg-Piezo1-/-), and the murine pancreatic α cell line αTC1-6. Expression of Proglucagon was investigated by real-time PCR and western blotting. Plasma glucagon and insulin were detected by enzyme immunoassay. RESULTS: Under both normal- and high-fat diet conditions, Gcg-Piezo1-/- mice exhibited increased pancreatic α cell proportion, hyperglucagonemia, impaired glucose tolerance, and activated pancreatic mTORC1 signaling. Activation of Piezo1 by its agonist Yoda1 or overexpression of Piezo1 led to decreased glucagon synthesis and suppressed mTOR signaling pathway in αTC1-6 cells. Additionally, the levels of glucagon in the medium were also reduced. Conversely, knockdown of Piezo1 produced opposite effects. CONCLUSION: Our study uncovers the regulatory role of the Piezo1 ion channel in α cells. Piezo1 influences glucagon production by affecting mTOR signaling pathway.


Subject(s)
Diet, High-Fat , Glucagon-Secreting Cells , Glucagon , Ion Channels , Mice, Knockout , Animals , Glucagon-Secreting Cells/metabolism , Glucagon/metabolism , Mice , Ion Channels/metabolism , Ion Channels/genetics , Diet, High-Fat/adverse effects , Male , Signal Transduction , Insulin/metabolism , Cell Line , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanotransduction, Cellular , Mice, Inbred C57BL , Proglucagon/metabolism , Proglucagon/genetics , Pyrazines , Thiadiazoles
17.
Am J Physiol Gastrointest Liver Physiol ; 326(6): G736-G746, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38625142

ABSTRACT

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.


Subject(s)
Blood Glucose , Hepatitis, Autoimmune , Insulin Resistance , Insulin , Humans , Female , Male , Middle Aged , Blood Glucose/metabolism , Cross-Sectional Studies , Adult , Insulin/blood , Hepatitis, Autoimmune/blood , Hepatitis, Autoimmune/metabolism , Hepatitis, Autoimmune/complications , Glucagon-Like Peptide 1/blood , Glucagon-Like Peptide 1/metabolism , Fatty Liver/metabolism , Fatty Liver/blood , Gastric Inhibitory Polypeptide/blood , Gastric Inhibitory Polypeptide/metabolism , Aged , Glucose Tolerance Test , Cholangitis, Sclerosing/blood , Cholangitis, Sclerosing/metabolism , Cholangitis, Sclerosing/complications , Glucagon/blood , Glucagon/metabolism , Liver Cirrhosis, Biliary/blood , Liver Cirrhosis, Biliary/metabolism , Liver Cirrhosis, Biliary/complications , C-Peptide/blood
18.
Front Endocrinol (Lausanne) ; 15: 1376530, 2024.
Article in English | MEDLINE | ID: mdl-38681771

ABSTRACT

Background/Objectives: Glucagon is important in the maintenance of glucose homeostasis, with also effects on lipids. In this study, we aimed to apply a recently developed model of glucagon kinetics to determine the sensitivity of glucagon variations (especially, glucagon inhibition) to insulin levels ("alpha-cell insulin sensitivity"), during oral glucose administration. Subjects/Methods: We studied 50 participants (spanning from normal glucose tolerance to type 2 diabetes) undergoing frequently sampled 5-hr oral glucose tolerance test (OGTT). The alpha-cell insulin sensitivity and the glucagon kinetics were assessed by a mathematical model that we developed previously. Results: The alpha-cell insulin sensitivity parameter (named SGLUCA; "GLUCA": "glucagon") was remarkably variable among participants (CV=221%). SGLUCA was found inversely correlated with the mean glycemic values, as well as with 2-hr glycemia of the OGTT. When stratifying participants into two groups (normal glucose tolerance, NGT, N=28, and impaired glucose regulation/type 2 diabetes, IGR_T2D, N=22), we found that SGLUCA was lower in the latter (1.50 ± 0.50·10-2 vs. 0.26 ± 0.14·10-2 ng·L-1 GLUCA/pmol·L-1 INS, in NGT and IGR_T2D, respectively, p=0.009; "INS": "insulin"). Conclusions: The alpha-cell insulin sensitivity is highly variable among subjects, and it is different in groups at different glucose tolerance. This may be relevant for defining personalized treatment schemes, in terms of dietary prescriptions but also for treatments with glucagon-related agents.


Subject(s)
Blood Glucose , Diabetes Mellitus, Type 2 , Glucagon , Glucose , Adult , Aged , Female , Humans , Male , Middle Aged , Administration, Oral , Blood Glucose/metabolism , Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Glucagon/blood , Glucagon-Secreting Cells/metabolism , Glucagon-Secreting Cells/drug effects , Glucose/metabolism , Glucose/administration & dosage , Glucose Intolerance/blood , Glucose Intolerance/metabolism , Glucose Tolerance Test , Insulin/blood , Insulin/administration & dosage , Insulin Resistance , Kinetics , Models, Theoretical
19.
Peptides ; 176: 171219, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38615717

ABSTRACT

People with obesity and type 2 diabetes have a high prevalence of metabolic-associated steatotic liver disease, hyperlipidemia and cardiovascular disease. Glucagon increases hepatic glucose production; it also decreases hepatic fat accumulation, improves lipidemia and increases energy expenditure. Pharmaceutical strategies to antagonize the glucagon receptor improve glycemic outcomes in people with diabetes and obesity, but they increase hepatic steatosis and worsen dyslipidemia. Co-agonism of the glucagon and glucagon-like peptide-1 (GLP-1) receptors has emerged as a promising strategy to improve glycemia in people with diabetes and obesity. Addition of glucagon receptor agonism enhances weight loss, reduces liver fat and ameliorates dyslipidemia. Prior to clinical use, however, further studies are needed to investigate the safety and efficacy of glucagon and GLP-1 receptor co-agonists in people with diabetes and obesity and related conditions, with specific concerns regarding a higher prevalence of gastrointestinal side effects, loss of muscle mass and increases in heart rate. Furthermore, co-agonists with differing ratios of glucagon:GLP-1 receptor activity vary in their clinical effect; the optimum balance is yet to be identified.


Subject(s)
Diabetes Mellitus, Type 2 , Glucagon-Like Peptide-1 Receptor , Glucagon , Obesity , Humans , Obesity/drug therapy , Obesity/metabolism , Glucagon/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/metabolism , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/pharmacology , Receptors, Glucagon/agonists , Receptors, Glucagon/metabolism
20.
Endocr J ; 71(3): 207-208, 2024.
Article in English | MEDLINE | ID: mdl-38538332

Subject(s)
Glucagon , Starvation , Humans , Insulin
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